Glaucoma is a chronic neurodegeneration of the optic nerve and one of the leading causes of vision loss in the world. The retinal ganglion cell (RGC) is the primary retinal cell type damaged in glaucoma, and investigations into death mechanisms have determined that RGCs die by apoptosis. Central to apoptosis is the activation of specific proteases, termed caspases. Caspases are central to neuronal execution and are activated in RGCs in a number of diseases and experimental models. Caspases are also activated in ocular hypertensive rat models of glaucoma. Our work has shown that caspase-3, a major effector of the apoptotic cascade, is activated in RGCs exposed to chronically elevated intraocular pressure. We have also shown activation of caspase-8, which initiates apoptosis after activation of "extrinsic" membrane- bound receptors of the tumor necrosis factor (TNF) superfamily. Caspase-9, which initiates apoptosis through "intrinsic" mitochondrial mechanisms, has also been implicated in experimental glaucoma. What is not well understood is which of the various caspases are most important in glaucomatous RGC death. The neurotrophin brain-derived neurotrophic factor (BDNF) acts through its cognate receptor tyrosine receptor kinase B (TrkB) as a survival and differentiation factor in both the developing and adult central and peripheral nervous system. Intraocular injection of BDNF prevents the degeneration of RGCs fourteen days after optic nerve transaction by suppressing caspase-3 activity. Virally-mediated gene delivery of BDNF or TrkB has demonstrated increased RGC survival in rodent models of optic nerve trauma and glaucoma. Although trophic factor withdrawal predominates in developmental apoptosis (the "neurotrophin hypothesis"), there is little evidence to implicate it as a primary apoptotic trigger in glaucoma. We hypothesize that apoptotic RGC death in glaucoma depends on reduction in neurotrophic support and on activation of caspases. We will explore these molecular events using a chronic ocular hypertensive model of mouse glaucoma. We will examine transgenic mouse lines that lack or under- express critical apoptosis and neurotrophin related factors, to determine susceptibility or resistance to chronic intraocular pressure elevations. The benefits from this work are that the critical steps operative in apoptosis of RGCs in glaucoma can be identified, and targeted neuroprotective strategies developed to treat glaucoma.